We have established the Midwest Hepatitis B Consortium, comprising investigators from several institutions with considerable expertise in hepatitis B, to act as a clinical center for the Hepatitis B Network. This consortium maximizes our access to patients with HBV infection for enrollment in Network studies. The consortium allows is to bring unique strengths to bear including having two pediatric hepatologists to develop and conduct studies in children with hepatitis B and a nationally recognized liver pathologist (Elizabeth Brunt M.D.) with the knowledge, equipment and expertise to scan and digitize liver biopsy slides from all subjects enrolled in Network studies. Specific aim 1 is to establish a database of HBsAg-positive subjects from all consortium sites. One aim of the database is to determine the proportion of patients with chronic HBV infection who initially meet criteria for antiviral therapy. Those who are not initially treated will be followed at 6 month intervals over the next 5 years to determine the proportion who reactivate and become eligible for treatment. The second specific aim is to conduct a randomized double-blind controlled trial of entecavir vs, tenofovir vs. the combination of these two agents for 4 yrs, with 1 yr of follow up with the primary endpoint being the proportion of patients at year 5 (1 year follow up after stopping therapy) in whom HBV DNA is undetectable in serum (PCR negative). The third specific aim is to conduct a series of ancillary studies aimed at answering key questions about chronic hepatitis B. We propose ancillary studies to be considered by the Network steering committee including a pilot, exploratory study of entecavir in children, aimed at determining the pharmacokinetics and optimal dosing because of the limited treatment options available to children with hepatitis B. We propose pilot, exploratory studies of treatment of under-studied groups including patients in the immune tolerant and inactive carrier phases of chronic hepatitis B. We propose virology studies to be carried out in collaboration with the Virology Center, including full length cloning of HBV isolates from each subject to study viral variables contributing to resistance and genetic covariance network analysis, as we have successfully done in hepatitis C. Finally, we propose studies on Health-Related Quality of Life (HRQOL) using the Hepatitis B Quality of Life instrument, version 1.0, HBQOL v1.0 developed and validated by Dr Fasiha Kanwal, consortium P.I. at the St. Louis VAMC.